A document by Nicola Curry. Click on the document to view its contents.

Background: Cervical cancer affects 3,197 women in the UK, and 604000 women worldwide annually, with peak incidence seen between 30-34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies may undermine future efforts for consistent evidence synthesis. Objectives: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. Search Strategy: We searched MEDLINE, EMBASE, and CENTRAL from inception to February 2019. Selection Criteria: Randomised controlled trials, cohort and observational studies, and case studies of more than 10 participants from January 1990 to date. Data Collection and Analysis: Study characteristics and all reported treatment outcomes. Main results: 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), post-operative complications (74/104), intra-operative complications (72/104), and quality of life (5). There were huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. Conclusions: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set (COS) is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians, and researchers. This systematic review sets the groundwork for the development of a COS for fertility sparing surgery in cervical cancer. Funding: British Medical Association’s Strutt and Harper Grant.

Abstract Objective: To investigate serum human epididymis-4 (HE4) as a predictive biomarker of intrauterine progestin response in endometrial cancer and atypical endometrial hyperplasia (AEH). Design: Prospective observational study. Setting: Consecutive sample of women attending a tertiary gynaecological oncology centre in the North West of England. Population: Women with AEH or early stage, low grade endometrial cancer who were unfit or declined primary surgical management; 48 in the discovery cohort and 28 in the validation cohort. Methods: Women were treated with a levonorgestrel intrauterine system (LNG-IUS) for 12 months. Endometrial biopsies and imaging were performed to assess treatment response. Pre-treatment serum HE4 was analysed by chemiluminescence immunoassay and diagnostic accuracy and logistic regression analyses performed. Main outcome measure: Progestin response at 12 months defined by histology and imaging. Results: Baseline serum HE4 was significantly higher in non-responders than responders in both discovery [134.6pmol/L (IQR:94.0-292.4) vs 76.5pmol/L (IQR:59.7-87.3), p<0.001] and validation cohorts [108.2pmol/L (IQR:80.3-119.2) vs 64.4pmol/L (IQR:53.0-73.0), p=0.004]. An HE4≥77pmol/L had a sensitivity and specificity for progestin treatment response of 83.3% and 53.3% in the discovery cohort, and 85.7% and 76.2% and in the validation cohort, respectively. When expressed as a continuous variable, the AUC was 0.81 (95%CI:0.67-0.95) and 0.87 (95%CI:0.73-1.00) for the discovery and validation cohorts, with every 1pmol/L of HE4 increasing the likelihood of progestin treatment failure by 2% and 5%, after adjustment for age and histology, respectively (p=0.02 and p=0.18). Conclusion: Serum HE4 shows promise as a predictive biomarker of progestin treatment response in endometrial cancer and AEH.

Mini Commentary on manuscript ID BJOG-22-0531.R1

Objective: To investigate reliable biomarkers for predicting histological chorioamnionitis (HCA). Design: In this retrospective study, PPROM mothers were treated with a course of dexamethasone. Blood tests for serum indictors were conducted continuously after first injection. Setting: One Shanghai hospital Population: PPROM mothers before 34 0/7 weeks of gestation Methods: Data were compared by General Linear Model analysis. The diagnostic accuracy in predicting HCA were evaluated with ROC curve. Main Outcome Measures: The response of infectious indictors to dexamethasone treatment; the diagnostic accuracy for CRP and PCT in predicting HCA. Results： We found 98 HCA women (62.42%) and 59 CON women (37.58%) in 157 PPROM mothers. WBC and neutrophil significantly increased 24 hours after the first injection in both groups, followed by a decrease at 72 hours post first injection (P<0.05). No significances were found between two groups in WBC, neutrophil and lymphocyte. Both CRP and PCT were significantly higher in the HCA group after first injection. PCT had both high specificity and sensitivity, especially at the baseline (cutoff, 0.031 ng/ml). Furthermore, the positive predictive values (PPV) of PCT were respectively 0.946 and 0.960 at 48 (cutoff, 0.049 ng/ml) and 72 (cutoff, 0.051 ng/ml) hours, which were better than the corresponding PPV of CRP. Conclusion: The response of WBC, neutrophil and lymphocyte to dexamethasone could be differentiated from uterine infection; PCT could be a reliable biomarker for early diagnosis of HCA. Funding: Shanghai Municipal Commission of Health and Family Planning (GWIV-26, 202040128); Pudong Commission of Health and Family Planning (PW2019D-13).

Commentary for manuscript BJOG 2022 Gurol-Urganci et al (10.1111/1471-0528.17193)

Background: Science integrity initiatives require specific recommendations for randomised clinical trials (RCT). Objective: To prepare a set of statements for RCT integrity through an international multi-stakeholder consensus. Methods: Following prospective registration (https://osf.io/bhncy, https://osf.io/3ursn), the consensus was developed via: multi-country multidisciplinary stakeholder group composition and engagement; evidence synthesis of 55 systematic reviews concerning RCT integrity; anonymised two-round modified Delphi survey with consensus threshold based on the average percent of majority opinions; and, a final consensus development meeting. Results: There were 30 stakeholders representing 14 countries from 5 continents including trialists, ethicists, methodologists, statisticians, consumer representative, industry representative, systematic reviewers, funding body panel members, regulatory experts, authors, journal editors, peer-reviewers and advisors for resolving integrity concerns. Delphi survey response rate was 86.7% (26/30 stakeholders). There were 111 statements (73 stakeholder-provided, 46 systematic review-generated, 8 supported by both) in the initial long list, with 8 additional statements provided during the consensus rounds. Through consensus the final set consolidated 81 statements (49 stakeholder-provided, 41 systematic review-generated, 9 supported by both). The entire RCT life cycle was covered by the set of statements including general aspects (n=6), design and approval (n=11), conduct and monitoring (n=19), reporting of protocols and findings (n=20), post-publication concerns (n=12), and future research and development (n=13). Conclusion: Implementation of this multi-stakeholder consensus statement is expected to enhance RCT integrity.

Objective To test equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. Design Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. Setting Single centre in Australia. Population 278 pregnant women with iron deficiency. Methods Participants received either 500 mg (n=152) or 1000mg (n=126) of intravenous ferric carboxymaltose in the second or third trimester. Main outcome measures The proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30ug/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth, and safety outcomes. Results The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)). Conclusions Administration of 1000mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500 mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.

Title Page Title: Letter to the Editor: ” Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo- controlled study ”.Article type : Letter to the editor.

Objective: To describe clinical and laboratory characteristics of term deliveries complicated by chorioamnionitis, and to assess their association with adverse neonatal outcomes. Design: Cross-sectional cohort study Setting: The study is based on data from the Swedish Pregnancy Register, enriched with clinical data extracted from medical charts. Population and Sample: A random sample of 500 term singleton deliveries in Stockholm County with registered diagnosis of chorioamnionitis in the Swedish Pregnancy Register between 2014 and 2020. Methods: Logistic regression was used to estimate odds ratios (OR) as a measurement of the association between clinical and laboratory characteristics and neonatal complications Main Outcome Measures: Neonatal infection and asphyxia-related complications. Results: Maternal fever, maternal and fetal tachycardia, and elevated inflammatory laboratory markers were frequent signs of chorioamnionitis. The prevalence of neonatal infection and asphyxia-related complications was 10 and 22%, respectively. First leukocyte count in the second tertile (OR 2.14 [95% CI 1.02-4.49]), maximum CRP level in the third tertile (OR 4.01 [95% Cl 1.66-9.68]), and positive cervical culture (OR 2.22 [95% Cl 1.10-4.48]) were associated with an increased risk of neonatal infection. Maximum level of CRP in the third tertile (OR 1.93 [95% Cl 1.09-3.41]), and fetal tachycardia (OR 1.63 [95% Cl 1.01-2.65]) were associated with increased risk of asphyxia-related complications. Conclusions: In addition to maternal intrapartum fever, maternal and fetal tachycardia, and elevated inflammatory laboratory markers were common signs of chorioamnionitis. Elevated inflammatory laboratory markers were associated with both neonatal infection and asphyxia-related complications, and fetal tachycardia was associated asphyxia-related complications.

Background A core outcome set could address inconsistent outcome reporting and improve evidence for stillbirth care research, which has been identified as an important research priority. Objectives To identify outcomes and outcome measurement instruments reported by studies evaluating interventions after the diagnosis of a stillbirth. Search strategy Amed, BNI, CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO, and WHO ICTRP from 1998 to August 2021. Selection criteria Randomised and non-randomised comparative or non-comparative studies reporting a stillbirth care intervention. Data collection and analysis Interventions, outcomes reported, definitions and outcome measurement tools were extracted. Main results 40 randomised and 200 non-randomised studies were included. 58 different interventions were reported, labour and birth care (52 studies), hospital bereavement care (28 studies), clinical investigations (116 studies), care in a multiple pregnancy (2 studies), psychosocial support (28 studies) and care in a subsequent pregnancy (14 studies). 391 unique outcomes were reported and organised into 14 outcome domains: labour and birth; postpartum; delivery of care; investigations; multiple pregnancy; mental health; emotional functioning; grief and bereavement; social functioning; relationship; whole person; subsequent pregnancy; subsequent children and siblings and economic. 242 outcome measurement instruments were used, with 0-22 tools per outcome. Conclusions Heterogeneity in outcome reporting, outcome definition and measurement tools in care after stillbirth exists. Considerable research gaps on specific intervention types in stillbirth care were identified. A core outcome set is needed to standardise outcome collection and reporting for stillbirth care research.

A document by Becky Liu. Click on the document to view its contents.

Objective To investigate perinatal mortality, morbidity and obstetric intervention after introducing universal third-trimester ultrasound scan for growth restriction. Design Prospective cohort study Setting Oxfordshire (OUH), UK Population Women with a non-anomalous singleton pregnancy undergoing pregnancy care and term delivery at OUH with an estimated-date-of-birth between 01/Jan/2014 and 30/Sept/2019. Methods Universal ultrasound for fetal growth restriction between 35+0 and 36+6 weeks was introduced in 2016. The outcomes of the next 18631 eligible term pregnancies were compared, using logistic regression, with the previous 18636 who had clinically-indicated ultrasounds only. ‘Screen positives’ for growth restriction were managed according to a pre-determined protocol. Main Outcome Measures Extended perinatal mortality, a composite of mortality or encephalopathy Grade II-III, and expedited birth. Other outcomes included composite adverse outcomes used elsewhere, detection of birthweight (<10th centile) and birth <39+0 weeks. Results Extended perinatal deaths decreased from 1.7/1000 to 1.2/1000 births (aOR: 0.73; 0.43 -1.25); mortality or severe morbidity decreased from 2.9/1000 to 1.9/1000 births (OR: 0.67; 0.44-1.03). Expedited births increased from 35.2% to 37.7% (OR: 1.08; 1.04 – 1.14). Birth prior to 39+0 weeks fell 10.5% (OR 0.89: 0.85 – 0.94). Birthweight (<10th centile) detection using fetal biometry alone was 31.4%, and rose to 40.5% if all abnormal scan parameters were used. Conclusion Introducing a universal ultrasound for growth restriction has limited impact on mortality and severe morbidity, but only small increases in intervention, and less early-term birth, are possible. The detection of birthweight (<10th c) improved where markers of growth restriction are used.

Objective: To explore the views of female genital mutilation (FGM) survivors, men, and healthcare professionals (HCPs) on the timing of deinfibulation surgery and NHS service provision. Design: Qualitative study informed by the sound of silence framework. Setting: Survivors and men were recruited from three FGM prevalent areas of England. HCPs and stakeholders were from across the UK. Sample: 44 survivors, 13 men and 44 HCPs. 10 participants at two community workshops and 30 stakeholders at a national workshop. Methods: Hybrid framework analysis of 101 interviews and three workshops. Results: There was no consensus across groups on the optimal timing of deinfibulation for survivors who wished to be deinfibulated. Within group, survivors expressed a preference for deinfibulation pre-pregnancy and HCPs antenatal deinfibulation. There was no consensus for men. Participants reported that deinfibulation should take place in a hospital setting and be undertaken by a suitable HCP. Decision making around deinfibulation was complex but for those who underwent surgery it helped to mitigate FGM impacts. Whilst there were examples of good practice, in general, FGM service provision was sub-optimal. Conclusion: Deinfibulation services need to be widely advertised. Information should highlight that the procedure can be carried out at different time points, according to preference, and in a hospital by suitable HCPs. Future services should ideally be developed with survivors, to ensure that they are clinically and culturally appropriate. Guidelines would benefit from being updated to reflect the needs of survivors and to ensure consistency in provision. Study registration number ISRCTN 14710507

Objectives: To evaluate risks of preterm birth and severe maternal morbidity (SMM) in female adolescent and young adult cancer survivors; assess maternal comorbidity as a potential mechanism; determine whether associations differ by use of assisted reproductive technology (ART). Design: Retrospective cohort Setting: Privately insured females in the U.S. Sample: Female with live births from 2000 to 2019 within OptumLabs®, a U.S. administrative health claims dataset Methods: Log-binomial regression models estimated relative risks of preterm birth and SMM by cancer status and tested for effect modification. Causal mediation analysis based on a counterfactual approach evaluated the proportions explained by maternal comorbidity. Main Outcome Measures: SMM, preterm birth Results: Among 46,064 cancer survivors, 2,440 singleton births, 214 multiple births, and 2,590 linked newborns occurred after cancer. In singleton births, preterm birth incidence was 14.8% in cancer survivors versus 12.4% in females without cancer (aRR 1.19, 95%CI 1.06-1.34); SMM incidence was 3.9% in cancer survivors versus 2.4% in females without cancer (aRR 1.44, 95%CI 1.13-1.83). Cancer survivors had more maternal comorbidities before and during pregnancy; 26% of the association between cancer and preterm birth and 30% of the association between cancer and SMM was mediated by maternal comorbidities. Associations between cancer and outcomes did not differ between ART and non-ART births. Conclusion: Preterm birth and SMM risks were modestly increased after cancer. Significant proportions of elevated risks may be due to increased comorbidities. Prevention and treatment of comorbidities provides an opportunity to improve perinatal outcomes among cancer survivors.

Clinician bias on the low resource workfloorThis is a mini commentary on R Goldenberg et al.,In this study in two LMIC settings in Asia, expert panels who looked at cause of death of premature neonates, with significantly more information available, found far more birth asphyxia and less Respiratory Distress Syndrome than the discharging NICU physicians did. Some NICU physicians attributed respiratory distress in the premature neonate to RDS by default, especially if there was no other information to contradict this belief. Especially in the Pakistan setting, birth asphyxia did not seem to be on the mind of the physician.What could be possible explanations?The maternal population, illiteracy rates, low rates of NICU admission and high death rates in the Pakistan setting suggest an impoverished background population and very restrained resources.In such setting one could easily imagine diagnostic means and treatment options are limited. If there is also lack of staff, reduced availability of beds, and work overload (ref: authors correspondence), priorities have to be made who to admit and who to treat. Life expectancy and quality of life may play a role in triaging.Physicians who work in labourward settings without CTGs may recognize the viewpoint that obstetric management only be guided by the maternal condition. On several SubSaharan African labourwards I experienced that decisions were not (solely) to be based on the supposed fetal condition. To perform ‘an unnecessary caesarean section’, or on the other hand to try and salvage the life of a baby who then turns out to be brain damaged after a poor start, was not seen as good obstetric care. A premature baby with apparent severe birth asphyxia might consequently not be transferred to the NICU. A baby who is admitted may not carry the diagnosis birth asphyxia since, as the authors point out this may imply mismanagement. It could even go further: if potential fetal compromise is not relevant in the obstetric management, it may also not be picked up. The obstetric physician could in such situation easily develop a blind spot for birth asphyxia.Another cause of clinician bias in such low resource settings could be underestimation of the gestation, making RDS a more likely diagnosis. If gestational scans are not available, and last menstrual periods are unreliable (associated with illiteracy) gestational age is more often estimated by fundal height at presentation in labourward, or by the birthweight of the baby. Underestimation could be the case in Pakistan where 65% of babies were thought to be less than 32 weeks, only 12,5 % of the neonates were thought to be growth restricted which is associated with birth asphyxia, but nearly 63 % suffered with birth asphyxia according to the panel.These are several hypotheses how physicians in a low resource setting could form biases in their clinical thinking, which, when not corrected by other information, could lead to incorrect diagnoses and mismanagement. This correcting information could come from diagnostic tools, such as PCR tests Xchest, etc,. However, sufficient time and systems in place for proper handovers, e.g. between the obstetrician and pediatrician, an open mind and awareness of pitfalls, audit and reflection on one’s management, and training to stay up to date are just as important. Hopefully expert panel studies such as these, could stimulate awareness and be a motor to improved Obstetric and Pediatric Care in LMIC settings.

Background Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. Objectives To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. Main results Twenty-six studies including 1921 patients were included, of which most were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from one day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (8 studies), heart rate (5 studies), electrocardiogram (ECG, 3 studies) and cardiac magnetic resonance imaging (MRI, 1 study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. Conclusions Administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear due to the small number of studies, study heterogeneity and mixed quality. Given the emerging preclinical evidence of harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS. Keywords: Antenatal corticosteroids, ACS, cardiovascular, offspring, blood pressure

Intrapartum stillbirths and early neonatal deaths remain stubbornly high in low income countries. Fetal monitoring in labour can reduce these poor outcomes, but limited progress is being achieved in these settings. Intermittent auscultation and continuous electronic fetal monitoring (CEFM) can both be employed to monitor a fetus during labour. There are challenges and limitations with both modalities. We used AI augmented fetal monitoring in a hospital in Malawi and demonstrated substantial reductions in both intrapartum stillbirths and early neonatal deaths with a small increase in the cesarean delivery rate. AI-CEFM should be studied further to achieve better perinatal outcomes.